KEYNOTE-177 Cements Pembrolizumab as New Standard of Care in MSI-H/dMMR mCRC

Thierry Andre, MD

Pembrolizumab (Keytruda) monotherapy has become the new frontline standard of care for patients with microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to findings from the phase 3 KEYNOTE-177 trial, said Thierry Andre, MD.

The results of the trial, which demonstrated a doubling in progression-free survival (PFS) with pembrolizumab versus standard chemotherapy in patients with newly diagnosed MSI-H mCRC, have also reinforced the importance of conducting biomarker-driven studies, said Andre.

At a median follow-up of 32.4 months, the median PFS was 16.5 months (95% CI, 5.4-32.4) with pembrolizumab (n = 153) versus 8.2 months (95% CI, 6.1-10.2) with standard chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 154) in patients with MSI-H/dMMR mCRC, translating to a 40% reduction in the risk of disease progression or death (HR, 0.60; 95% CI, 0.45-0.80; P = .0004).¹

“It's very rare to see an improvement in PFS of this magnitude in gastrointestinal oncology,” said Andre, who is lead author of the study

The 2-year PFS rates were 48.3% in the pembrolizumab arm versus 18.6% in the chemotherapy arm. Additionally, the duration of response was not reached in the pembrolizumab arm versus 10.6 months in the chemotherapy arm.

“[These data suggest that] we have an opportunity to cure some patients with immunotherapy,” said Andre.

On June 29, 2020, the FDA approved the PD-1 inhibitor for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR CRC, based on data from the KEYNOTE-177 trial.²

In an interview with OncLive, Andre, professor of medical oncology, University Pierre et Marie Curie (UMPC), and head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discussed the results of the KEYNOTE-177 trial in mCRC.

OncLive: Could you provide some background on the study?

Andre: The current standard of care is chemotherapy plus or minus cetuximab (Erbitux), panitumumab (Vectibix), or bevacizumab (Avastin). However, the outcomes with these regimens are not as good in the MSI-H population as they are in the microsatellite stable population.

Four years ago, phase 2 data were published in the New England Journal of Medicine regarding the use of pembrolizumab in MSI-H CRC. This was a very important paper that demonstrated the efficacy of pembrolizumab in this patient population. We also have the results of the phase 2 KEYNOTE-164 trial, which showed good results with pembrolizumab in pretreated patients.

MSI-H tumors have a lot of neoantigens and a high tumor burden, so there’s a lot of rationale to use immunotherapy in these patients.

Could you elaborate on the initial findings that were seen in the phase 2 trials?

The results of the phase 2 trials were pretty good with incredible long-term control. However, without a phase 3 trial, it’s difficult to get an indication. As such, we launched the phase 3 trial in the first-line setting versus standard of care chemotherapy.

What did the results of the phase 3 trial show?

The results showed an improvement in PFS, which was the primary end point of the trial, at 16.5 months with pembrolizumab versus 8.2 months with chemotherapy. The hazard ratio was 0.6, translating to a 40% improvement in PFS and a highly significant P value.

At the beginning, we did see a crossover of the curves. Around 30% of the patients didn’t respond to pembrolizumab. However, at 24 months, 48% of the patients in the pembrolizumab arm discontinued treatment and remain progression free. In the chemotherapy arm, the 2-year PFS rate was [approximately] 19%.

The overall survival (OS) data are not yet mature, so they weren’t presented. Patients in the chemotherapy arm did crossover to the pembrolizumab arm. More than half of the patients who received chemotherapy went on to receive pembrolizumab or another anti–PD-1 in the second-line setting, which we know can influence OS. OS will be analyzed when more than 190 events occur.

How was pembrolizumab tolerated in the trial?

The toxicity profile of both regimens favors pembrolizumab. The rate of grade 3/4 toxicities was 22% with pembrolizumab versus 66% with chemotherapy. It’s not the same toxicity. With pembrolizumab, we see mainly immune toxicity versus the traditional adverse effects of chemotherapy.

Notably, pembrolizumab was given as a 1-hour infusion every 3 weeks, whereas the administration schedule for chemotherapy is more complex. Pembrolizumab is more convenient for patients.

Are there any unanswered questions that you would like to see addressed in the future?

We would like to understand why 50% of patients progressed in the trial. We’d also like to evaluate combination regimens with anti–CTLA-4 agents or chemotherapy to try to improve upon these findings. We already know the combination of PD-1 inhibition and CTLA-4 inhibition is better than PD-1 inhibition alone.

Then, there is the possibility of [using this regimen] as neoadjuvant or adjuvant therapy in patients with stage II/III disease.

What is the current utility of biomarkers in this space?

It’s critical to select patients for pembrolizumab according to MSI status. In doing so, we can offer them a good drug with pretty good results. You can test for MSI with immunohistochemistry or polymerase chain reaction.

What is your take-home message for your colleagues?

Pembrolizumab should be the frontline standard of care for patients with MSI-H mCRC. Biomarker-driven studies are really the best way to improve outcomes for patients.

What research efforts in this space are you excited about?

In CRC, I’m very excited by the immune-oncology data with anti–PD-1 plus anti–CTLA-4 agents. In the neoadjuvant setting, in MSI-H tumors, especially in gastric cancer, we can really change the prognosis of patients [with the use of immunotherapy]. It’s possible to achieve a complete histological response [with immunotherapy], which we showed in a study that was recently published by the Dutch team. It’s clear that we’re entering a new paradigm in CRC.

References

1. FDA approves Merck’s Keytruda (pembrolizumab) first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. News release. Merck. June 29, 2020. Accessed August 3, 2020. bwnews.pr/3ePxyfu.
2. Andre T. Shiu Kai-Keen, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(suppl 15):LBA4. doi:10.1200/JCO.2020.38.15_suppl.LBA4